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Objective: To examine the incidence and risk factors for analcancer in a multicenter cohort of human immunodeficiency virus (HIV) positive and HIV-negative men who have sex with men followed between 1984 and 2006 (Multicenter AIDS Cohort Study).

Results: There were 28 cases of analcancer among the 6972 men who were evaluated. The incidence rate was significantly higher in HIV-positive men than in HIV-negative men (incidence rate = 69 vs 14 per 100,000 person-years). Among HIV-positive men, analcancerincidence was higher in the highly active antiretroviral therapy (HAART) era than the pre-HAART era (incidence rate = 137 vs 30 per 100,000 person-years). In multivariate analysis restricted to the HAART era, analcancer risk increased significantly with HIV infection (relative hazard = 4.7, 95% confidence interval = 1.3 to 17) and increasing number of unprotected receptive anal sex partners at the first 3 study visits (P trend = 0.03). Among HIV-positive men, current HAART use did not decrease analcancer risk.

Conclusions: HIV-positive men had increased risk of analcancer. Improved survival of HIV-positive individuals after HAART initiation may allow for sufficient time for human papillomavirus-associated anal dysplasias to develop into malignancies, thus explaining the increased incidence of analcancer in the HAART era.

From the *Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; †University of California at Los Angeles School of Nursing, Los Angeles, CA; ‡Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL; §Department of Molecular Microbiology and Immunology, John Hopkins Blamberg School of Public Health, Baltimore, MD; and ‖Department of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA.

INTRODUCTION

The incidence of analcancer has increased in the past decade,1 particularly in certain population subgroups. Human immunodeficiency virus (HIV) positive men and men who have sex with men (MSM) are at increased risk of analcancer compared with the general population.2-4 HIV-negative MSM have an estimated incidence rate (IR) of 35/100,000,5 which is comparable to the incidence of cervical cancer in the general female population before widespread cervical Pap screening was introduced (40-50 cases/100,000)6 and greater than the current incidence of cervical cancer (6-15/100,000).1,2 The incidence of analcancer among HIV-positive MSM is thought to be even higher (~70-100 cases/100,000).7 As HIV-positive men are living longer after the introduction of highly active antiretroviral therapy (HAART), cancer poses a larger problem for this population.

Recent evidence suggests that anal infection with human papillomavirus (HPV) is strongly associated with the subsequent development of analcancer.8-11Anal HPV infection is believed to be sexually transmitted, and cross-sectional studies suggest that a higher number of sexual partners is associated with an increased odds of anal dysplasia12 and analcancer.5,9,13Sexual risk behaviors are believed to serve as a surrogate for anogenital HPV infection,14 likely explaining the association of these behaviors with cancer risk. Longitudinal analysis to establish a temporal relationship between high-risk sexual behaviors and subsequent risk of analcancer has not been reported.

The cancer subsites in the anus and rectum most likely to have an HPV etiology have not been thoroughly evaluated. Studies of analcancer have used varying inclusion criteria for cancer site based on differing surgical and histological definitions of the boundaries of the anal canal. Most studies included rectal2,9,15 and perianal skin9,15,16 cancers in their “analcancer” case definitions which could attenuate results by including etiologically heterogeneous cancers. Although HPV is known to infect squamous cells and the majority of anal cancers are squamous cell carcinomas (SCCs), few studies17 have focused exclusively on the epidemiology of anal SCC. Results from rectalcancer studies have varied, with some suggesting low9 and others a high18,19 HPV prevalence in rectal adenocarcinomas. HPV has been recently shown to be an important cause of cervical adenocarcinomas,11,20 so it is possible that HPV may play a role in rectal adenocarcinomas as well.

The natural history of anal HPV infection and cofactors for persistence of anal HPV infection are not well understood. In addition, the effects of HIV-associated immunosuppression and HAART on analcancer risk are not well described. Recent studies have suggested that the incidence of analcancer in HIV-positive individuals is higher in the HAART era than the pre-HAART era3,17 and that anal HPV persistence and progression of HPV-associated precancers are not reduced in those on HAART.21,22

This manuscript describes the incidence of, and risk factors for, analcancer using longitudinal data from HIV-positive and HIV-negative men in the Multicenter AIDS Cohort Study (MACS). This is one of the first studies to evaluate incidence or risk factors for analcancer using exposure information collected before the cancer diagnosis.

METHODS

Study Population

The study included all men in the MACS, a cohort that has been described elsewhere.23-25 In brief, the MACS includes primarily HIV-positive and HIV-negative MSM and has study sites in Baltimore, Chicago, Los Angeles, and Pittsburgh. The study began in 1984 and a total of 6972 men have been enrolled over 3 separate enrollment periods (1984-1985, 1987-1991, and 2001-2003). Analcancer cases included only men with T1 invasive anal or rectal disease.

Outcomes

Subject self-report of cancer was verified by histology report. Histology reports and medical records were collected, reviewed, and summarized by trained abstractors and centrally rereviewed for this paper. Tumor specimens were not available for histological review, testing, or adjudication for these analyses.

Incident anal (ICD-O = 154.2-154.8 or ICD-O3 = 21.0-21.8), perianal (ICD-O3 = 44.5 with record noting perianal location), and rectal (ICD-O = 154.0-154.1 or ICD-O3 = 19.9-20.9) ICD codes were classified together as analcancer for these analyses. Cases were classified using documented pathology reports (n = 23) or physician narrative indicating diagnosis of analcancer (n = 1). Where no medical documentation was available, self-report of analcancer by study subject was accepted (n = 4). Subanalysis using only those cancers with anal tumor site and squamous cell morphology (ICD-O code 8052-8084 or ICD-03 = 8070.2-8078) was also performed, and these cancers are referred to as anal squamous cell carcinomas (ASCCs); only T1 invasive cancers confirmed by pathology report review were included in the ASCC subanalysis. Data gathered between 1984 and March 2007 were included in these analyses.

Exposures

Detailed behavioral data were collected from participants every 6 months using interviewer-administered and/or audio computer-assisted self-interview format. Recent sexual behaviors assessed at each visit included the number of total, anal insertive, anal receptive, and unprotected anal receptive sexual partners in the past 6 months. The number of unprotected anal receptive partners “at baseline” was chosen for this analysis due to the long latency period between HPV infection and development of cancer and the expectation that more distant measures of sexual risk better represent current risk of malignancy. A summary measure of baseline sexual risk was created by adding the number of recent unprotected anal receptive partners reported at each of the 3 initial study visits. Recent tobacco use was also assessed at each visit as tobacco use has been associated with elevated anal HPV prevalence, viral load,26 and odds of analcancer.15

Self-reported use of antiretroviral medications at each visit was summarized to define whether participants were using HAART. The definition of HAART was guided by the Department of Health and Human Services/Kaiser Panel28 guidelines and defined as follows: (a) 2 or more nucleoside reverse transcriptase inhibitors (NRTIs) in combination with at least one protease inhibitor (PI) or 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) (89% of observations classified as HAART); (b) 1 NRTI in combination with at least one PI and at least one NNRTI (5%); (c) a regimen containing ritonavir and saquinavir in combination with 1 NRTI and no NNRTIs (1%); and (d) an abacavir- or tenofovir-containing regimen of 3 or more NRTIs in the absence of both PIs and NNRTIs (5%), except for the 3 NRTI regimens consisting of abacavir, tenofovir and lamivudine OR didanosine, and tenofovir and lamivudine. Combinations of zidovudine and stavudine with either a PI or NNRTI were not considered HAART.

Semiannual visits also included standardized physical examinations, medical histories, and phlebotomy for laboratory measurements and storage of cells, serum, and plasma in centralized repositories. Medical records were sought and reviewed for confirmation of all reported acquired immunodeficiency syndrome (AIDS) defining illnesses, cancers, and other specified conditions. Passive and active methods were used to ascertain deaths, and information on causes of death was captured by death certificate review.

Statistical Methods

Poisson regression models were used to calculate analcancer IRs. Given the very long follow-up involved in this study, reasons for right censoring (ie, time when follow-up ended) varied between the original and more recently recruited participants in the MACS. More than two thirds (69%) of men enrolled in 2001-2003 remained in active follow-up as of September 2006 compared with only 27% of those whose baseline visit was before 2001. At the time of analysis, death (64% vs 4%, respectively) was much more common among HIV-positive men enrolled before 2001 than among similar men who were more recently enrolled.

Cox proportional hazard models were used to calculate the relative hazard (RH) for risk factors of interest. Study entry (baseline) was used as the time origin, and men were at risk up to the date of analcancer diagnosis, last date of contact, or March 30, 2007, whichever came first. Tobacco use, current HAART use, nadir CD4 cell count, and HIV viral load were evaluated as time-updated covariates in these models. Trends in risk were tested by modeling ordinal variables as single, continuous, independent variables.

Kaplan-Meier curves were generated using age as the timescale and assuming analcancer-free time from study entry back to age 30 years. HIV-positive participants who contributed time before 1996 were included in a “HIV+, pre-HAART era” curve, with exit age at the date of analcancer, last date of contact, or December 31, 1995, whichever came first. HIV-positive participants who contributed time after 1996 were included in a “HIV+, HAART era” curve, with entry age at January 1, 1996. Thus, HIV-positive men who were enrolled before 2001 and still enrolled and analcancer free in 1996 contributed to both pre-HAART and HAART era curves.

Given the large proportion of men in the original MACS cohort who died before HAART became available, competing risks could affect interpretation of longitudinal analysis.

Many men early in the epidemic died before having the “opportunity” to develop cancer but still contributed time to the longitudinal analysis. To address this concern, we performed a nested case-control study.

Case-control analysis was performed using conditional logistic regression. Each analcancer case was individually matched to 3 controls using the following matching criteria: age at diagnosis (±5 years), year of study enrollment, HIV serostatus, ever/never HAART use, and follow-up time (+2.5 years). Follow-up time was defined as the time from study entry until analcancer diagnosis for HIV-negative and HIV-positive HAART-naive participants. HIV-positive cases who used HAART before their cancer diagnosis were matched to controls on the time of HAART initiation (±3 years) and time from first HAART use until diagnosis (±2.5 years). Cases who were HIV seropositive at study entry were also matched by CD4 cell count at study entry (±50 cells/μL) to account for duration of infection. Cases with incident HIV during the study were matched with HIV-prevalent participants with baseline CD4 counts >750 cells/μL due to unavailability of seroconverters as matched controls. All analyses were performed using SAS 9.1 (Cary, NC). Graphical illustrations were generated by S-plus 6.2 (Insightful Corporation, Seattle, WA).

RESULTS

Description of Cancers

Between 1984 and March 2007, 28 anal, perianal, or rectal (hereafter referred collectively as anal) cancers were observed among the 6972 men in the MACS cohort. This included 21 anal cancers of which 17 were SCC, 1 was neuroendocrine, and 3 had unconfirmed morphology. Of the 7 rectal cancers included, 5 were adenocarcinomas and 2 were SCCs. Six anal cancers were diagnosed among HIV-negative men, and 22 were diagnosed among HIV-positive men (Table 1). More than half (67%; 4 of 6) the anal cancers in HIV-negative men were rectal adenocarcinomas compared with only 14% (3 of 22) of anal cancers in HIV-positive men (P < 0.001). Anal cancers in HIV-positive men were twice as likely to have squamous morphology (68% vs 33%) as cancers in HIV-negative men (P = 0.034). The median age at cancer diagnosis was 47.4 years in HIV-positive and 57.8 years in HIV-negative men. The median follow-up time for men enrolled between 1984-1991 and 2001-2003 was 10.5 and 3.9 years, respectively. Participants enrolled earlier in the study were more likely to have died (34.2% vs 2.7%, P < 0.001) and equally likely to have been lost to follow-up (29.5% vs 28.4%, P = 0.19) than participants enrolled in 2001-2003.

Cases occurred throughout the 22-year follow-up period, including 9 cases in the pre-HAART (1984-1995) and 19 in the HAART (1996-2006) era. Age, HIV viral load, and CD4 cell count at diagnosis varied considerably (Table 1). HIV-positive anal cases included both men with suppressed HIV viral RNA and high CD4 cell count and severely immunocompromised men. Among HIV-positive cases, half were diagnosed with an AIDS-defining condition at time of their analcancer diagnosis (Table 1). This proportion was higher among HIV-positive cases in the pre-HAART (4 of 5) than the HAART era (7 of 17). When diagnosed with analcancer, 27% of the HIV-positive cases were HAART naive. However, this included men who developed cancer in the pre-HAART era. Of the 16 cases which occurred in the HAART era, 15 (94%) started HAART before their cancer diagnosis.

Time-to-Event Analysis

Risk factors for analcancer were explored using time-to-event analysis. In univariate analysis, risk of analcancer increased nonsignificantly with increasing age (P trend = 0.15). Men with 7 or more unprotected anal receptive sexual partners at the first 3 study visits had significantly higher risk of analcancer (RH = 2.7, 95% CI = 1.08 to 6.5) compared with men with no unprotected receptive anal sex partners. Additionally, a dose-response trend was suggested by significantly increasing risk with increasing number of unprotected receptive anal sex partners (P trend = 0.03, Table 2). Consistent with this finding, the median number of unprotected receptive anal sex partners reported in the initial 3 study visits was significantly higher in analcancer cases than in other study participants (P = 0.018, Fig. 1). Results were similar when the sexual risk behavior analyzed was number of unprotected receptive anal sex partners reported in the 6 months before baseline (P trend = 0.06) or lifetime number of sexual partners reported at baseline (P trend = 0.07). In analysis limited to confirmed ASCC, history of more than 100 lifetime sexual partners was similarly associated with increased cancer risk (hazard ratio = 5.5, 95% CI = 0.67 to 44) but did not reach statistical significance due to the smaller number of cases.

HIV-positive men had a significantly higher risk of analcancer (RH = 5.1, 95% CI = 2.1 to 12.6) or confirmed ASCC (RH = 10.4, 95% CI = 2.1 to 50) than HIV-negative men. Among HIV-positive men, analcancer risk was significantly elevated in men with nadir CD4 cell count <200 cells/μL (RH = 3.3, 95% CI = 1.4 to 7.9) but was not associated with HIV viral load (Table 2). Risk of analcancer was also significantly higher in ever-smokers than never-smokers (RH = 3.9, 95% CI = 1.2 to 12.8), but there was no evidence of increasing risk with current dose of tobacco used (Table 2).

To evaluate whether HAART therapy had an effect on analcancer risk, we considered both ever and current HAART use. In analysis restricted to data during the HAART era, risk of analcancer was elevated but was not significantly different in HIV-positive current HAART users and nonusers (RH = 1.8, 95% CI = 0.5 to 6.4) or HIV-positive ever and never HAART users (RH = 1.7, 95% CI = 0.23 to 13). In contrast, risk of rectal adenocarcinomas was more than 4-fold lower among ever than never HAART users (RH = 0.22, 95% CI = 0.02 to 3.13), suggesting a possible decrease in risk of these cancers with HAART use.

As age is an important risk factor for analcancer, we further evaluated the difference in analcancer risk in the HAART and pre-HAART eras using a Kaplan-Meier curve to examine risk in each era by participants' age (Fig. 2). These data suggest greater cancer risk (ie, shorter time to analcancer) among HIV-positive than HIV-negative men (P < 0.001). These differences were more pronounced in the HAART than the pre-HAART era. Among HIV-positive men, analcancer risk for younger men (younger than 50 years) was similar in the HAART and pre-HAART eras. However, as age increased above 50 years of age, HIV-positive men in the HAART era seem to have more risk of analcancer than HIV-positive men in the pre-HAART era (P = 0.16, Fig. 2). Evaluation of the difference in cancer risk among HIV-positive men at older ages is limited by the smaller number of men available for analysis in the older age categories. Considerably fewer HIV-positive men from the pre-HAART enrollment lived to contribute data at ages above 60 years (n = 36 men) compared with men alive in the HAART era (n = 115 men).

Due to the high mortality in the pre-HAART era and the difference in analcancer risk in the HAART and pre-HAART eras and to better evaluate analcancer risk factors, we restricted multivariable analysis to time and events contributed by participants in the HAART era (1996 onward). In the multivariate analyses of all men in the HAART era, risk of analcancer was elevated in participants with HIV infection (RH = 4.7, 95% CI = 1.3 to 17) and men with more unprotected anal receptive sex partners at the first 3 study visits (P trend = 0.03). As HIV infection was an important risk factor, the effect of other risk factors was then evaluated in analysis limited to HIV-positive participants. Number of unprotected anal receptive sexual partners at the initial 3 study visits (P trend = 0.014; Table 3) remained strongly associated with increased analcancer risk in this analysis. Nadir CD4 cell count and ever tobacco use were associated with elevated but not statistically significant increased cancer risk (Table 3). As only one HAART era analcancer case was HAART naive at time of analcancer diagnosis, the effect of “ever” HAART use could not be evaluated in this model. Current HAART use, race, and age were not associated with increased cancer risk. Results were similar when restricted to ASCC (data not shown).

Case-Control Analysis

Risk factors identified in univariate case-control analysis were consistent with those observed in longitudinal analysis (Table 2). The effect of HIV, HAART, and age could not be evaluated because these factors were used for matching cases and controls. However, after controlling for these factors through matching, number of unprotected anal receptive sex partners at the first 3 study visits (P trend = 0.027) was associated with significantly increased odds of analcancer. Nadir CD4 <200 cells/μL [odds ratio (OR) = 1.6, 95% CI = 0.54 to 4.5] and ever tobacco use (OR = 3.6, 95% CI = 0.78 to 16.9) were associated with elevated but not statistically significant increased odds of analcancer.

In multivariate analyses of all subjects, the odds of analcancer were elevated in those with 7 or more anal receptive sex partners reported at the first 3 study visits (P trend = 0.05), ever-smokers (OR = 4.5, 95% CI = 0.89 to 23), and HIV-positive men with nadir CD4 <200 cells/μL (OR = 2.1, 95% CI = 0.65 to 6.6). Results were similar when restricted to HIV-positive men (Table 3) or to ASCC (data not shown).

DISCUSSION

Registry data suggest higher analcancerincidence among HIV-positive than among HIV-negative individuals (relative risk = 10-352)17,29-35 and increasing analcancer rates in the past few decades1,17,36; however, few longitudinal studies have evaluated analcancerincidence.37,38 The cohort study presented here utilized 22 years of longitudinal data from a well-characterized multicenter cohort study population with high participant retention. MACS data have an additional strength, compared with registry data, in that the exposure information analyzed was collected before cancer diagnosis. This study demonstrates significantly higher incidence of analcancer in HIV-positive than in HIV-negative MSM. Consistent with the temporal trend of increasing analcancerincidence suggested in several studies,1,36,39-42 this study found significantly higher analcancerincidence in the HAART era (1996-2006) than the pre-HAART era (1984-1995). This trend is likely related to premature mortality witnessed in the pre-HAART period among HIV-positive men. In the MACS, the median age for diagnosis of AIDS before 1995 was 39 years,43 whereas the median age for analcancer is above 50 years.44 Other explanations for the increase in analcancerincidence could include a direct toxic effect of HAART or incomplete adjustment for the aging of the study cohort. Improved diagnosis or reporting of these cancers is less likely but cannot be excluded. Thus, analcancerincidence may continue to increase in this population as HAART improves survival, thus allowing HIV-positive MSM to survive long enough to develop analcancer.

Observed IRs among HIV-positive men in this study were comparable to those reported in other studies of HIV-positive persons in the HAART era (92-144 per 100,000 person-years) and pre-HAART era (12-69 per 100,000 person-years).17,36,37 Discrepancies between estimates may be partially explained by heterogeneity in definitions of which cancer subsites and morphologies are included as anal cancers and inclusion or exclusion of in situ cancers. Incidence of analcancer among the high-risk HIV-negative men in this study was higher than IRs reported in some population-based samples during the same time period (0.4-0.8 and 1.0 per 100,000 person-years in pre-HAART and HAART eras, respectively36,39-42) but similar to estimates in 2 other studies during a similar time period.36,41

Sexual risk behaviors at study entry were strongly associated with risk of subsequently developing analcancer in this study, supporting an HPV etiology to these cancers. This is consistent with the results of analcancer case-control studies, which have shown increased odds of analcancer in those with higher number of sexual partners,5,9,15 ever receptive anal sex partners,5,13,15 and number of receptive anal sex partners.16 Associations with sexual risk are likely attenuated in this study as most MACS participants were older than 30 years at study entry, and it is highly likely that many of the men were exposed to HPV before study entry. It takes many years from HPV infection to development of cancer, and as some of the analcancer cases in this study occurred only a few years after study entry, the baseline sexual behaviors in these men may not be representative of their sexual risk when initially infected with HPV. Sexual risk behavior was similarly associated with analcancer risk when rectal cases were included and when limited to only ASCC, suggesting that some rectal cancers may have an HPV-associated etiology.

As suggested in this study, tobacco use has been associated with increased odds of analcancer (OR = 1.9-7.7) in most case-control studies of analcancer.15,16,45,46 This study may have been underpowered to detect the effect of tobacco and did not have a measure of lifetime tobacco use. Sexual behavior is strongly associated with tobacco use,47,48 so residual confounding by sexual behavior could explain the observed moderate associations between tobacco and analcancer risk. However, increased risk of other HPV-associated malignancies has also been observed in tobacco users,45,49,50 suggesting a possible effect of tobacco on HPV persistence or progression of HPV-associated dysplasias to cancer. The effect of tobacco may be small in relation to the effect of HIV and may therefore be harder to observe in a population of HIV-positive individuals.

Although cervical cancer is considered an AIDS-defining illness, analcancer currently is not. However, studies suggest that individuals with HIV infection are at increased risk of anal high-grade squamous intraepithelial lesions7,51,52 and, as shown in this and other studies, at increased risk of analcancer.2,29,35 Although HAART has reduced the risk of many HIV-associated morbidities,53 initial studies suggest that HAART does not decrease risk of HPV-associated anal, genital, and oropharyngeal cancers.2,21,53,54 Longitudinal analysis of the effect of HAART on anal HPV progression is limited but shows no apparent effect of HAART on anal HPV natural history,22,55 and cross-sectional analysis demonstrates a high prevalence of anal HPV infection in HIV-positive men despite HAART-related immune restoration.22,56 In this study, analcancer cases that occurred during the HAART era were primarily in men currently on HAART. Many of these men had low HIV viral load and CD4 cell counts above 200 cells/μL, suggesting HAART-related immune restoration may not be effective (or may have a modest effect) against progression of anal HPV-associated cellular abnormality. As HAART leads to improved survival for HIV-positive individuals, it may thus allow sufficient time for development of invasive anal disease. Analcancerincidence in individuals on HAART may therefore continue to rise.

This study was limited by the lack of tumor tissue for HPV DNA testing. Central pathology review of all cancers was also not possible although detailed review of existing pathology reports was performed to reduce misclassification. Longitudinal data were included from men enrolled into the MACS cohort in 3 different waves with variable characteristics and follow-up time. Additionally, baseline measures of sexual risk behaviors were used in this study, and as these may be after the peak time of sexual risk taking in some men, these measures may not accurately represent the behaviors when the men were most as risk at HPV infection.

Analcancerincidence has increased significantly in the past 10 years and is currently estimated to be ~2.0 per 100,000 in the general US population.1 MSM and HIV-positive individuals have substantially higher rates of analcancer.57Analcancer may be preventable, but the benefits of screening for and treating anal cancers have not yet been well evaluated. Further research is needed to determine the benefits and costs of risk reduction interventions, screening, and treating analcancer precursors in high-risk populations such as HIV-positive individuals.

28. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents: Henry J Kaiser Family Foundation Panel on Clinical Practices for the Treatment of HIV Infection; October 2004 Revision. http://www.aidsinfo.nih.gov.